Prostaglandins in which a methylene unit has been replaced by an oxygen have received considerable attention in the past. A number of 7-oxa analogs of the primary prostaglandins have been synthesized and generally they are known to exhibit substantial biological activity. See, e.g., R. G. McDonald-Gibson, J. D. Flack and P. W. Ramwell, Biochem. J., 132,117 (1973). Typical examples of the biological activities shown include inhibition of PGE.sub.1 induced smooth muscle contractions at various concentrations, inhibition of PGE.sub.2 biosynthesis, inhibition of arachidonic acid induced platelet aggregation, and the like. In earlier literature, Fried, et al. have synthesized a wide variety of monocyclic prostaglandin analogs in which the C-7 methylene has been replaced by oxygen. See Fried, J.; Santhankrishnan, T.; Himizu, J.; Lin, C.-H.; Ford, S. Nature 1969, 223, 208; Fried, J.; Mehra, M.; Kao, W.; Lin, C.-H, Tetrahedron Lett. 1970, 2695; Fried, J.; Mehra, M.; Kao, W. J. Am. Chem. Soc. 1971, 93, 5544; Fried, J.; Lin, C.; Mehra, M.; Kao, W.; Delven, P. Ann. N.Y. Acad. Sci. 1971, 180, 38; McDonald-Gibson, R. G.; Flack, J. D.; Ramwell, P. W. Biochem. J. 1973, 132, 117.
In view of the variety of activities of the compounds reported by Fried, the applicant has as a primary objective of the present invention, developed a new synthesis for bicyclic and tricyclic analogs of 7-oxa PGH.sub.2.
In addition, the applicant has not only discovered a new high yield and direct synthesis technique for 7-oxa prostaglandin endoperoxide analogs, but has also discovered that one can selectively make either a bicyclic analog or a tricyclic analog, simply by the presence or absence of diisopropylethylamine in one of the reaction steps. This surprising discovery has not heretofore been known.
Accordingly, it is a primary objective of the present invention to prepare bicyclic and tricyclic 7-oxa prostaglandin endoperoxide analogs, which have a wide variety of biological activities.
A yet further objective of the present invention is to provide a synthesis technique for the preparation, selectively, of either bicyclic or tricyclic endoperoxide analogs, with the control of the synthesis of either a bicyclic or tricyclic being determined by, simply, the presence or absence of an organic amine, preferably diisopropylethylamine in one key reaction step.
A further objective is to provide a selective synthesis for bicyclic and/or tricyclic 7-oxa prostaglandin endoperoxide analogs which will progress in a high yield fashion to the desired synthesis products.
A further objective is to prepare a series of novel bicyclic and tricyclic 7-oxa prostaglandin endoperoxide analogs which exhibit a variety of biological activities, evidencing usefulness as pharmacological and potentially therapeutically active compounds.